Drug safety is a major concern for pharmaceutical groups, regulatory bodies, basic researchers and particularly patients. Safe and effective drugs maximize successful clinical outcomes and patient compliance. This project will provide unique tools for detecting drugs that have potential to induce the dangerous outcome phospholipidosis early in the drug development process and will identify patients that may be susceptible to this dangerous adverse event.
Drug safety is a major concern for patients taking medicines as well as pharmaceutical companies, regulatory bodies, and basic researchers. Drug induced phospholipidosis (DIPL) is an adverse reaction to cationic amphiphilic drugs (CADs) resulting in excessive phospholipid accumulation, a condition called phospolipidosis (PL), which in serious cases leads to organ failure and death. The occurrence of DIPL is prevalent reflected by amiodarone, a commonly used anti-arrythmic drug. Approximately 50% of patients prescribed amiodarone will develop DIPL, requiring 17% of those affected to cease treatment. Amiodarone is representative of CADs which make up a significant fraction of both approved drugs and chemical compounds currently in various phases of pre-clinical development. While tools are available for screening of many potential adverse events, such as cytochrome P450 and hERG channel inhibition, PL-inducing potential of drug candidates is hindered by laborious low-throughput methods that have been judged unsatisfactory by the FDA. This is especially problematic for those cases where only CADs are available as therapeutic options. Lysosomal phospholipase A2 (LPLA2) is a phospholipid processing enzyme central to DIPL. Inhibition of LPLA2 activity induces PL in cells, yet an enzymatic assay that would enable high-throughput screening (HTS) of candidate compounds was unavailable until the completion of the Phase I portion of this project. The result of the successful Phase I component of this project was development of an HTS assay that successfully identified 95% of known PL-inducing drugs as inhibitors of LPLA2 using purified enzyme. This Phase II application will adapt the assay developed in Phase I to enable evaluation of LPLA2 levels and activity in biological samples to establish levels of each that are indicative of healthy and diseased patients, data that is heretofore unavailable given the lack of tools. When these levels are established, patient samples will be screened for PL-susceptibility using samples from ongoing clinical studies. At the conclusion of this project, levels and activity of LPLA2 associated with diseased states will be established for the first time, in addition to the development and release of new products that will have the ability to serve as companion diagnostics to identify patients that are susceptible t PL and as tools to screen for PL-inducing potential of drug candidates early on the discovery process, ultimately leading to decreased drug costs and improved patient outcomes. With approximately one-third of all drugs entering clinical trials failing because of toxicity and safet concerns, early detection of DIPL would decrease health care costs by identifying drugs that will induce DIPL prior to expensive clinical trials. The specific application to personalized medicine will identify individuals who are susceptible to DIPL for a given drug and guide treatment, thereby preventing patient harm and improving the efficiency of healthcare in the U.S.